This project is based on a multidisciplinary, international collaboration to study the role of cannabinoid receptors and the endocannabinoid system in behavior, pharmacology and physiology of cognitive function. The collaboration entails an unprecedented approach to the study of long-term effects of cannabinoid CB1 receptor agonists, inverse agonists/antagonists and neutral antagonists. Specific studies for this project will address several issues of concern necessary for the effective use of preclinical models (i.e. EEG) and novel cannabinoid antagonists that are translational and can be directly applied across species from rodent to human. These tools will be utilized to probe cannabinoid involvement in anxiety, stress and sleep cycle to enrich our understanding of no The project will (1) utilize 24-hr EEG monitoring in rats to examine the consequences of chronic exposure to cannabinoid CB1 receptor agonists and antagonists on the sleep cycle with respect to behavior and neural function;(2) compare effective routes of administration of cannabinoid agonists and antagonists;and (3) examine several novel antagonists with respect to rat behavior and hippocampal neural activity. The proposed experiments will thus extend studies of systemic and local infusion of cannabinoid CB1 receptor agonists and antagonists on neural activity mediating spatial memory in rats. These Aims will provide important new techniques for examining long-term consequences of exposure to cannabinoid agonists (as positive controls) vs. antagonists - including novel inverse agonists, neutral antagonists and modulators that are just now becoming available for research use. The project includes translational aspects by incorporating techniques that can bridge studies in rats, mice and humans. The scope of this project has been reduced from the original 5-year plan, and the specific Aims have been changed to focus on two specific techniques (EEG and route of administration) and one preliminary scientific investigation (behavioral and electrophysiological effects of novel cannabinoid antagonists).